Triple negative breast cancers (TNBC), the breast cancer subtype that lacks expression of the HER2, estrogen, and progesterone receptors, represent the tumor type with the poorest outcome due to its highly proliferative phenotype, early metastasis, and remains without targeted agents. Thus, this cancer type still represents a critical challenge to treat in the clinic. While involved in the multi-institutional I-SPY breast cancer trials, the Goga Lab discovered that the oncogene MYC is: 1) disproportionally highly-expressed in the TNBC subtype, 2) associated with poor patient outcome, and 3) can be the basis of targeted therapies. Using an unbiased screen, we recently identified an under-appreciated kinase, PIM1 a kinase whose inhibition selectively stops the growth of breast tumor cells that display high MYC, such as TNBC. Notably, inhibitors of the Proviral integration site for Moloney Murine leukemic virus (PIM) kinases are currently being tested in the clinic. There is great interest to better delineate mechanisms for how PIM inhibition stops TNBC growth. We have intriguing preliminary data that suggests PIM regulates metabolic pathways required for primary tumor growth and metastasis. The central hypothesis of this proposal is that PIM supports metabolic programs required for TNBC and its inhibition dysregulates metabolic processes necessary for primary tumor growth and metastatic cell survival. We seek to use our pre-clinical models of TNBC to discover metabolic pathways regulated by PIM and determine if targeting these pathways stops tumor growth and progression. My preliminary data suggests nucleotide synthesis is upregulated in TNBC primary tumor growth. In Aim 1: Investigate effects of PIM-dependent changes in nucleotide availability on TNBC progression, I propose to study the regulation of pyrimidine and purine synthesis and/or salvage pathways by PIM and test whether PIM inhibition is synergistic with existing therapies that require nucleotide metabolism. Additionally, PIM1 expression in patient samples is positively associated with distant-metastasis in TNBC. My preliminary data suggests abrogating PIM activity decreases metastasis. I predict PIM regulates important metabolic processes in metastasis. In Aim 2: Elucidate PIM?s regulation of metabolic pathways in metastatic TNBC, I will determine whether PIM regulates important metabolic processes that are necessary for metastatic cell growth and survival. My goal for this fellowship is to uncover new molecular mechanisms behind TNBC requirement for PIM, which will support clinical trials to optimize combining PIM inhibitor with other targeted agents. Additionally, completion of the proposed work will help me develop the skills necessary to take steps towards applying for an independent investigator position at an academic institution to continue research in cancer biology and metabolism.